Preparation method of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3-(4H) ketone

Abstract

The invention relates to a preparation method of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3-(4H) ketone, and belongs to the technical field of pesticides. The reaction formula is as follows: # imgabs0 #; the method comprises the following steps: taking 1, 5-difluoro-2, 4-dinitrobenzene as a raw material, and carrying out etherification reaction on the 1, 5-difluoro-2, 4-dinitrobenzene and butyl glycolate under the action of a catalyst I and a calcium-containing inorganic substance; then carrying out hydrogenation reaction under the action of a catalyst II to obtain 6-amino-7-fluoro-2H-1, 4-benzoxazine-3-(4H) ketone; the calcium-containing inorganic matter is at least one of calcium carbonate, calcium hydroxide or calcium oxide; the hydrogenation reaction pressure is 1-2 Mpa. Calcium-containing inorganic matters are added in the etherification reaction, and the hydrogenation reaction reduces the reaction pressure, so that the yield of the two-step reaction is increased to about 85%; and the purity of the product is improved to 97% or above. The preparation process is short, operation is easy and convenient, and large-scale production of flumioxazin is easier.

Description

Technical Field

[0001] The invention relates to the technical field of pesticides, and in particular to a method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one. Background Art

[0002] Fluazifop-butyl is an N-phenylphthalimide herbicide that mainly controls broadleaf weeds in soybean, sugarcane, cotton and many other crop fields. The herbicide has many advantages such as high efficiency, low toxicity, safety to non-target organisms and low environmental pollution. 6-Amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one is a key intermediate of fluazifop-butyl, and there are many methods for its synthesis. At present, the literature reports that there are three main synthetic routes for this compound: Route 1: Using m-fluorophenol as the starting material, it is prepared through etherification, nitration, and hydrogenation reduction. The intermediate fluorophenol in this route is expensive, the ether bond is easily broken during the nitration process, there are many side reactions, and the reaction yield is low. The reaction formula is as follows: .

[0003] Route 2: 2-nitro-5-fluoro-phenol is used as the starting material, and is prepared by etherification, hydrogenation cyclization, nitration, and hydrogenation reduction. This route requires two hydrogenation reductions, which greatly increases the cost and is not conducive to industrial production. The reaction formula is as follows: .

[0004] Route 3: Using 1,5-difluoro-2,4-dinitrobenzene as the starting material, it is obtained through etherification and hydrogenation. This synthetic route is short, and one-step hydrogenation achieves closed loop and reduction, which greatly reduces the cost and is conducive to industrial production; however, the etherification reaction has many by-products and is easy to introduce diether impurities, resulting in a low total yield of the two steps of etherification and hydrogenation, which has certain restrictions on industrial production. The reaction formula is as follows: .

[0005] Since Route 3 has the advantages of short synthesis route, low cost and the prospect of industrial production, many companies use Route 3 as the production route for production. The existing synthesis methods of Route 3 are reported as follows: (1) Patent CN110627738A discloses that 1,5-difluoro-2,4-dinitrobenzene and isopropyl chloroacetate are used as raw materials, N,N-dimethylformamide is used as solvent, and the temperature is raised to 90-150°C in the presence of potassium hydroxide, and the temperature is kept for reaction for 3 hours, and then the temperature is lowered and filtered, and the filtrate is distilled under reduced pressure to recover the solvent, thereby obtaining the product 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester. The yield of this step is 91% and the purity is 95%. Then, in an oxygen-free autoclave, 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester, N,N-dimethylformamide, and a cerium-modified nickel-based catalyst were added, the temperature was raised to 100°C, the pressure was 1.0 MPa, and hydrogen was passed through the autoclave for 3-4 hours. After the reaction was completed, the temperature was lowered and the pressure was released. The autoclave was transferred to a flask, the solvent was recovered, the temperature was lowered, methanol was added to reflux and the temperature was kept for 0.5 hours, and the temperature was lowered and filtered to obtain 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)one. The yield of this step was 92% and the purity was 98%.

[0006] In the above method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, the total yield of the two-step reaction is 83.72%, which has certain advantages, but has disadvantages such as high etherification reaction temperature, harsh reaction conditions, complex post-processing operations, and high costs.

[0007] (2) Patent CN105837563B discloses that a mixed solution of triethylamine, butyl glycolate and dichloroethane is slowly added dropwise to a dichloroethane solution of 1,5-difluoro-2,4-dinitrobenzene under stirring, the reaction temperature is controlled at 0-5°C, water is added to quench the reaction after completion, the organic phase is separated and washed with sodium hydroxide solution to evaporate the dichloroethane, thereby obtaining 3-fluoro-4,6-dinitrophenoxyacetic acid butyl ester. The yield of this step is 89.9% and the purity is 90.1%. Then, methanol and Pd / C catalyst are added to an oxygen-free autoclave, the temperature is raised to 70-95°C, the pressure is 3-3.5 MPa, hydrogen is introduced, and 3-fluoro-4,6-dinitrophenoxyacetic acid butyl ester dissolved in methanol is added dropwise under stirring, and the reaction temperature is controlled to be 90-95°C; after the reaction is completed, the pressure is released and the discharged material is filtered with a catalyst filter, 35% concentrated hydrochloric acid is added to the filtrate, and the salt is centrifuged to obtain a crude solid product; then, the crude solid product is dissolved in soft water, decolorized with activated carbon, and alkali washed and crystallized to obtain 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, and the yield of this step is 84% ​​and the purity is 96.1%.

[0008] In the above method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, the total yield of the two-step reaction is 75.51%, and the reaction yield still needs to be improved. In addition, the hydrogenation pressure is high in the hydrogenation step, and more impurities are generated, which affects the purity of the product. At the same time, there are also disadvantages such as complex post-processing operations and high costs. Summary of the invention

[0009] In view of the problems of harsh reaction conditions and more impurities in the preparation of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, an intermediate of fluazifop-propyl, the present invention provides a method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one to solve the above problems. The present invention adopts route three, adds calcium-containing inorganic substances in the etherification step, reduces the reaction pressure in the hydrogenation step, improves the total yield of the two-step reaction, and improves the purity of the product to more than 98%.

[0010] The technical solution of the present invention is as follows: A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, the reaction formula is as follows: ; 1,5-difluoro-2,4-dinitrobenzene is used as a raw material, and an etherification reaction is carried out with butyl glycolate under the action of catalyst I and a calcium-containing inorganic substance to obtain a solution containing butyl 3-fluoro-4,6-dinitrophenoxyacetate; then a hydrogenation reaction is carried out under the action of catalyst II to obtain 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one; catalyst I is at least one of triethylamine, N,N-diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); catalyst II is one of palladium carbon or Raney nickel; the calcium-containing inorganic substance is at least one of calcium carbonate, calcium hydroxide or calcium oxide; and the hydrogenation reaction pressure is 1-2Mpa.

[0011] Furthermore, the calcium-containing inorganic substance is calcium carbonate.

[0012] Furthermore, the molar ratio of 1,5-difluoro-2,4-dinitrobenzene to the calcium-containing inorganic substance is 1:0.95~1.05.

[0013] Furthermore, the molar ratio of 1,5-difluoro-2,4-dinitrobenzene to butyl glycolate is 1:1 to 1.2.

[0014] Furthermore, the mass ratio of 1,5-difluoro-2,4-dinitrobenzene to catalyst I is 1:0.08~0.10; the mass ratio of 1,5-difluoro-2,4-dinitrobenzene to catalyst II is 1:0.08~0.10.

[0015] Furthermore, a solvent is added to the etherification reaction, and the solvent is one of methyl isobutyl ketone, DMF (N,N-dimethylformamide) or toluene.

[0016] Furthermore, the etherification reaction temperature is 0~5°C.

[0017] Furthermore, the hydrogenation temperature is 80-100°C.

[0018] The beneficial effects of the present invention are: The present invention adds a calcium-containing inorganic substance as a base in the etherification reaction, and adds a small amount of amine as a catalyst. Compared with the prior art, the amount of amine used is greatly reduced. In addition, the cost of the calcium-containing inorganic substance is relatively low, and the yield is significantly improved while the cost of raw materials is greatly reduced. The reaction pressure is reduced in the hydrogenation reaction, and the generation of impurities during the reaction is effectively reduced, so that the purity of the product is increased to more than 97%, and the yield of the two-step reaction is increased to more than 85%; more importantly, the preparation process of the present invention is short, the operation is simple and convenient, especially the etherification process omits the steps of post-treatment and solvent removal, realizes the integration of etherification and hydrogenation, has low production cost, and is easier to mass-produce fluazifop-butyl. DETAILED DESCRIPTION

[0019] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0020] Example 1 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480kg DMF, 120kg 1,5-difluoro-2,4-dinitrobenzene, 41.35kg calcium hydroxide and 6.07kg N,N-diisopropylethylamine to the etherification reactor, cool the reaction system to 0~5°C, and then slowly drop 77.65kg butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0021] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, and the atmosphere was replaced with nitrogen three times, then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, DMF was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 90.19 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 98.0% (area normalized) by HPLC and a yield of 83.4%.

[0022] Example 2 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of DMF, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 41.35 kg of calcium hydroxide and 6.07 kg of 1,8-diazabicyclo[5.4.0]undec-7-ene to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0023] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, and the atmosphere was replaced with nitrogen three times, then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, DMF was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 89.59 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 97.6% (area normalized) according to HPLC, and a yield of 82.5%.

[0024] Example 3 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480kg DMF, 120kg 1,5-difluoro-2,4-dinitrobenzene, 41.35kg calcium hydroxide and 6.07kg triethylamine into the etherification reactor, cool the reaction system to 0~5℃, and then slowly drop 77.65kg butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection shows that 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0025] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, and the atmosphere was replaced with nitrogen three times, then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, DMF was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 91.32 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 98.3% (area normalized) according to HPLC, and a yield of 84.7%.

[0026] Example 4 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 41.35 kg of calcium hydroxide and 6.07 kg of triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0027] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, the atmosphere was replaced with nitrogen three times, hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, DMF was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 91.56 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, the purity of which was 98.5% (area normalized) by HPLC, and the yield was 85.1%.

[0028] Example 5 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg toluene, 120 kg 1,5-difluoro-2,4-dinitrobenzene, 41.35 kg calcium hydroxide and 6.07 kg triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0029] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, the atmosphere was replaced with nitrogen three times, hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, DMF was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 90.07 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, with a purity of 97.9% (area normalized) according to HPLC, and a yield of 83.2%.

[0030] Example 6 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg toluene, 120 kg 1,5-difluoro-2,4-dinitrobenzene, 41.35 kg calcium hydroxide and 6.07 kg triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0031] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation high-pressure reactor, 9.6 kg of Raney nickel was added, and the gas was replaced with nitrogen three times, then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the reactor no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing reactor, DMF was recovered under reduced pressure, and methanol was added to the residue in the reactor, the temperature was raised to reflux and kept warm for 20 minutes, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 90.19 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 98% (area normalized) by HPLC and a yield of 83.4%.

[0032] Example 7 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 55.88 kg of calcium carbonate and 6.07 kg of triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is completed, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of methyl isobutyl ketone, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a methyl isobutyl ketone solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0033] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, the atmosphere was replaced with nitrogen three times, hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, methyl isobutyl ketone was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 91.79 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, the purity of which was 98.6% (area normalized) by HPLC, and the yield was 85.4%.

[0034] Example 8 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 31.29 kg of calcium oxide and 6.07 kg of triethylamine into the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is completed, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of methyl isobutyl ketone, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a methyl isobutyl ketone solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0035] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, the atmosphere was replaced with nitrogen three times, hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, methyl isobutyl ketone was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 91.20 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, the purity of which was 98.2% (area normalized) by HPLC, and the yield was 84.5%.

[0036] Example 9 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 55.88 kg of calcium carbonate and 6.07 kg of triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is completed, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of methyl isobutyl ketone, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a methyl isobutyl ketone solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0037] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation high-pressure reactor, 9.6 kg of Raney nickel was added, and the gas was replaced with nitrogen three times, and then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was kept warm until the pressure in the reactor no longer decreased, the pressure was released and the temperature was lowered, and the supernatant was transferred to a hydrogenation desolventizing reactor, and methyl isobutyl ketone was recovered under reduced pressure. Then methanol was added to the residue in the reactor, the temperature was raised to reflux and kept warm for 20 minutes, and the temperature was slowly lowered to room temperature. The reaction was centrifuged and dried to obtain 92.79 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 98.8% (area normalized) according to HPLC, and a yield of 86.5%.

[0038] Example 10 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 41.35 kg of calcium hydroxide and 6.07 kg of triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is complete, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of DMF, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a DMF solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0039] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation high-pressure reactor, 9.6 kg of Raney nickel was added, and the gas was replaced with nitrogen three times, and then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was kept warm until the pressure in the reactor no longer decreased, the pressure was released and the temperature was lowered, and the supernatant was transferred to a hydrogenation desolventizing reactor, and DMF was recovered under reduced pressure. Then methanol was added to the residue in the reactor, the temperature was raised to reflux and kept warm for 20 minutes, and the temperature was slowly lowered to room temperature. The reaction was centrifuged and dried to obtain 91.67 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 98.5% (area normalized) according to HPLC, and a yield of 85.2%.

[0040] Comparative Example 1 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene and 6.07 kg of triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is completed, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of methyl isobutyl ketone, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a methyl isobutyl ketone solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0041] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, and the atmosphere was replaced with nitrogen three times, and then hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was kept warm until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, methyl isobutyl ketone was recovered under reduced pressure, and then methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 minutes, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 82.73 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, with a purity of 97.1% (area normalized) according to HPLC, and a yield of 75.8%.

[0042] By comparing with Example 7, Comparative Example 1 shows that without adding calcium carbonate, the yield and content are greatly reduced. It is speculated that the higher yield of adding calcium carbonate is due to the synergistic effect of calcium carbonate and amine catalysts.

[0043] Comparative Example 2 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 55.88 kg of calcium carbonate and 6.07 kg of triethylamine to the etherification reactor, cool the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is completed, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of methyl isobutyl ketone, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a methyl isobutyl ketone solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0044] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, the atmosphere was replaced with nitrogen three times, hydrogenated to 1.0 MPa, heated to 90°C, and the pressure was increased to 2.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, methyl isobutyl ketone was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 87.13 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, the purity of which was 97.8% (area normalized) by HPLC, and the yield was 80.4%.

[0045] By comparing with Example 7, Comparative Example 2 shows that the pressure in the hydrogenation reaction is too high, and impurities generated during the process affect the product content and further affect the reaction yield.

[0046] Comparative Example 3 A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, which is as follows: (1) Add 480 kg of methyl isobutyl ketone, 120 kg of 1,5-difluoro-2,4-dinitrobenzene, 34.48 kg of potassium hydroxide and 6.07 kg of triethylamine into the etherification reactor, reduce the temperature of the reaction system to 0-5°C, and then slowly drop 77.65 kg of butyl glycolate. After the dropwise addition is completed, keep the reaction warm. HPLC detection of 1,5-difluoro-2,4-dinitrobenzene is ≤1.0%. Centrifuge to remove the salt residue, rinse the salt residue with a small amount of methyl isobutyl ketone, and wash the obtained organic phase with sodium bicarbonate aqueous solution until neutral to obtain a methyl isobutyl ketone solution of 3-fluoro-4,6-dinitrophenoxyacetic acid isopropyl ester.

[0047] (2) The reaction liquid obtained in step (1) was transferred to a hydrogenation autoclave, 9.6 kg of palladium carbon was added, the atmosphere was replaced with nitrogen three times, hydrogenated to 0.8 MPa, heated to 90°C, and the pressure was increased to 1.0 MPa after the pressure stabilized. The reaction was carried out by heat preservation until the pressure in the autoclave no longer decreased, the pressure was released and the temperature was lowered, the supernatant was transferred to a hydrogenation desolventizing autoclave, methyl isobutyl ketone was recovered under reduced pressure, and methanol was added to the residue in the autoclave, the temperature was raised to reflux and kept warm for 20 min, the temperature was slowly lowered to room temperature, and centrifuged and dried to obtain 85.76 kg of 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H) ketone, the purity of which was 97.5% (area normalized) by HPLC, and the yield was 78.9%.

[0048] By comparison with Example 7, Comparative Example 3 shows that by replacing calcium carbonate with potassium hydroxide, the product yield obtained by integrating the two steps of etherification and hydrogenation is 78.9%, which is significantly lower than that of the examples of the present invention.

[0049] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily conceive of changes or substitutions within the technical scope disclosed by the present invention, and such changes or substitutions shall be within the scope of protection of the present invention.

Claims

1. A method for preparing 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one, characterized in that: The reaction formula is as follows: ； 1,5-difluoro-2,4-dinitrobenzene is used as a raw material, and an etherification reaction is carried out with butyl glycolate under the action of catalyst I and a calcium-containing inorganic substance to obtain a solution containing 3-fluoro-4,6-dinitrophenoxyacetic acid butyl ester; then a hydrogenation reaction is carried out under the action of catalyst II to obtain 6-amino-7-fluoro-2H-1,4-benzoxazine-3-(4H)-one; catalyst I is at least one of triethylamine, N,N-diisopropylethylamine or DBU; catalyst II is one of palladium carbon or Raney nickel; the calcium-containing inorganic substance is at least one of calcium carbonate, calcium hydroxide or calcium oxide; and the hydrogenation reaction pressure is 1-2Mpa.

2. The preparation method according to claim 1, characterized in that The calcium-containing inorganic substance is calcium carbonate.

3. The preparation method according to claim 1, characterized in that: The molar ratio of 1,5-difluoro-2,4-dinitrobenzene to the calcium-containing inorganic substance is 1:0.95~1.

05.

4. The preparation method according to claim 1, characterized in that: The molar ratio of 1,5-difluoro-2,4-dinitrobenzene to butyl glycolate is 1:1-1.

2.

5. The preparation method according to claim 1, characterized in that: The mass ratio of 1,5-difluoro-2,4-dinitrobenzene to catalyst I is 1:0.08~0.10; the mass ratio of 1,5-difluoro-2,4-dinitrobenzene to catalyst II is 1:0.08~0.

10.

6. The preparation method according to claim 1, characterized in that: A solvent is also added in the etherification reaction, and the solvent is one of methyl isobutyl ketone, DMF or toluene.

7. The preparation method according to claim 1, characterized in that: The etherification reaction temperature is 0~5℃.

8. The preparation method according to claim 1, characterized in that: The hydrogenation temperature is 80~100℃.

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